1,2,4-Benzothiadiazines

ABSTRACT

Novel 1,2,4-benzothiadiazines substituted by an oxo group in the 3-position and substituted in the 4-position with hydrogen, lower alkyl, amino-lower alkyl, mono- or di-lower alkyl amino-lower alkyl, or imino-lower alkyl, are useful as central nervous system depressants, and as diuretics.

United States Patent [191 Sowinski et al.

[ Dec. 16, 1975 [54] 1,2,4-BENZOTHIADIAZINES [75] Inventors: FrancisAlexander Sowinski, Edison,

N.J.; B. Richard Vogt, Yardley, Pa.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: Oct. 31, 1973 21 Appl. No.: 411,547

[52] US. Cl. 260/243 D; 424/246 [51] Int. Cl. C07D 285/22 [58] Field ofSearch 260/243 D [56] References Cited UNITED STATES PATENTS 11/1967 deStevens et a1 260/243 D 9/1972 Yale 260/243 D OTHER PUBLICATIO NS Barneset al., J. C. S. Chem. Cumm. 1973 (20) 776-777.

Primary Examiner-Nicholas S. Rizzo Attorney, Agent, or FirmLawrence S.Levinson; Merle J. Smith; Donald J. Barrack [57] ABSTRACT 11 Claims, NoDrawings 1,2,4-BENZOTHIADIAZINES BRIEF DESCRIPTION OF THE INVENTIONCompounds having the structure:

and their pharmaceutically acceptable acid-addition salts, have usefulpharmacological activities. In formula I, and throughout thespecification, the symbols are as defined below:

R is lower alkyl; amino-lower alkyl; monoor dilower alkyl aminoloweralkyl; or imino-lower alkyl wherein the imino group has the formulawhere Z is oxygen, 'ClI-R (R is hydrogen, phenyl, or benzyl), or N-R (Ris hydrogen, lower alkyl, phenyl, or phenyl substituted with halogen,lower alkyl, lower alkoxy, or trifluoromethyl), n is 1, 2 or 3, and m is2 or 3;

R is phenyl or phenyl substituted with halogen, nitro, trifluorometh'yl,lower alkyl, or lower alkoxy;

R is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, orlower alkoxy; and

R, is hydrogen or r am -N Z are aziridinyl, azetidinyl, diazetidinyl,oxazetidinyl, isoxazolindinyl, imidazolyl, pyrrolidino, piperidino,piperazino, N-alkylpiperazino, N-phenylpiperazino, morpholino,pyrimidinyl, azepinyl, octahydroazocinyl, etc. The 5 and 6 memberedrings are preferred.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I,wherein R is other than hydrogen and lower alkyl, are central nervoussystem depressants and may be used as tranquilizers for the relief ofanxiety and tension states, for example in mice, rats, dogs and othermammalian species, in the same manner as chlordiazepoxide. For thispurpose these compounds may be incorporated in a conventional dosageform such as tablet, capsule, injectable or the like, along with thenecessary carrier material, excipient, lubricant, buffer or the like,for oral or parenteral administration in single or divided doses ofabout I to mg./kg./day, preferably about 5 to 15 mg./kg., two to fourtimes daily.

The compounds of formula I are diuretics, and as such, are useful in thetreatment of hypertension in mammals. They may be formulated inconventional dosage form such as tablet, capsule, injectable or thelike, along with the necessary carrier material, excipient, lubricant,buffer or the like, for oral or parenteral administration in single ordivided doses of from about I to I00 mg./kg./day, preferably 3 to 12mg./kg./day.

The compounds of formula I wherein R is hydrogen are prepared usingacids having the formula:

as the starting material. Compounds of formula II are known; see, forexample, Coll. Czech. Chem. Commun., 33, 1852 (1968), J. Org. Chem, 38,20(1973) and references cited therein.

The acid of formula II is converted to the corresponding acid chloridehaving the formula:

III

using means well known in the art. For example, an acid of formula IImay be reacted with either thionyl chloride, phosphorous trichloride, orphosphorous pentachloride. The conversion may be carried out in anorganic solvent, e.g., benzene, at elevated tempera tures.

The acid chloride of formula III can be converted to an acetophenonederivative having the formula:

by reacting it with ethoxy-magnesium diethyl malonate in an inertorganic solvent, such as ethyl ether, under reflux conditions for aperiod of time ranging from about 1 hour to 24 hours, preferably 2 hoursto 4 hours, and subsequently hydrolyzing the resulting complex withsulfuric acid and heating to decarboxylate the intermediate acylationproduct.

The compound of formula IV is oxidized to the corresponding sulfoxide,i.e.,

( i-CH using a mild, selective oxidizing agent such as sodium periodate.The oxidation reaction is run at a temperature of from about 0C to 85C,preferably 30C to 50C, for about 24 hours to days, preferably 5 days to7 days, in an organic solvent such as glyme.

Reaction. of the 2-( substituted sulfinyl)acetophenone of formula withhydrazoic acid yields a mixture of products having the formulas:

2 VI R3 \NH NHCCH and The reaction is run in an organic solvent,preferably a halogenated hydrocarbon such as chloroform, at atemperature of from about 30C to +55C, preferably 30C to 50C. Inaddition to the hydrazoic acid, a strong mineral acid such as sulfuricacid, is also present.

The product mixture made up of compounds of formulas VI and VII ishydrolized to yield a 2-(substituted sulfonimidoyl) aniline derivativehaving the formula:

VIII

The hydrolysis reaction is carried out under reflux conditions in anaqueous solution of base such as sodium or potassium hydroxide. Thecompound of formula VIII is converted into an acid-addition salt,preferably one that is physiologically acceptable. Exemplary salts arethe hydrohalides, sulfate, nitrate, phosphate, tartrate, maleate,fumarate, citrate, succinate, methanesulfonate, benzenesulfonate,toluenesulfonate and the like.

Ring closure of the acid-addition salt of the compound of formula VIIIis accomplished by reacting the salt with 1,1 -carbonyldiimidazole in aninert organic solvent, such as, o-dichlorobenzene at reflux temperaturefor about 1 hour to 24 hours, preferably 1 hour to 3 hours. Theresulting compound has the structure:

Compounds of formula IX are novel intermediates and as such theyconstitute a part of this invention.

Reaction of the substituted 1,2,4-benzothiadiazin- 3(4H)-one, l-oxide offormula IX with a compound of the formula:

are obtained using compounds of the formula:

as starting materials. The compounds of formula XI are prepared usingmethods described in Chem. Ber., 39, 3597ff (1906) and in US. Pat. No.3,188,320 issued June 8, 1965 to Sowinski et al.

The aniline derivative of formula XI is first reacted with aceticanhydride under reflux conditions for about 5 minutes to 8 hours,preferably 15 minutes to 1 hour. The reaction is run in an organicsolvent, preferably a halogenated hydrocarbon such as chloroform. A basesuch as pyridine is added to the reaction mixture. The resultingacetanilide has the formula:

The acetanilide of formula XII is reacted with chlorosulfonic acid in anorganic solvent such as o-dichlorobenzene at a temperature of from about0C to 180C, preferably C to C for a period of time ranging from about 10minutes to 16 hours, preferably 1 hour to 3 hours, and yields achlorosulfonyl substituted acetanilide having the formula:

XII

xIv 3 XIII 9 NHCCH3 v c1 -s g The sulfamylacetanilide of formula XIV isoxidized using a mild, selective oxidizing agent such as sodiumperiodate to yield a compound of the formula:

NHCCH Reaction may be carried out in glyme by slowly adding an aqueoussolution of the oxidizing agent to the sulfamylacetanilide. Followingcompletion of the addition of the oxidizing agent, the mixture isstirred for a period of time ranging from 24 hours to 240 hours,preferably 72 hours to 120 hours, while heating under reflux conditions.

The compound of formula XV is hydrolized using an aqueous solution ofbase such as potassium or sodium hydroxide. The compound of formula XVis dissolved in an aqueous base and heated at reflux temperature for aperiod of time ranging from 1 hour to 5 hours,

preferably 2 hours to 4 hours. The product has the formula:

XVI

The compound of formula XVI is reacted with hydrazoic acid in an organicsolvent, preferably a halogenated hydrocarbon such as chloroform, at atemperature of from about '30C to 55C, preferably 30C to 50C. Inaddition to the hydrazoic acid, a mineral acid such as sulfuric acid, isalso present. The resultant product has the formula:

0 I XVII R S NH 5? H NH Ring closure of the compound of formula XVII isaccomplished by reacting the compound with 1,1 '-carbonyldiimidazole anda halogenated aromatic solvent such as o-dichlorobenzene at refluxtemperature for about 1 hour to 24 hours, preferably 1 hour to 2 hours.The resultant compound has the structure:

Compounds of formula XVIII are novel intermediates and as such theyconstitute a part of this invention.

The 1 ,2,4-benzothiadiazine-3( 4I-I)-one-l-oxide of formula XVIII ismixed with benzyl chloroformate and an alkali metal carbonate such assodium or potassium carbonate in an organic sovlent such as acetone andheated under reflux conditions for a period of time of from about 1 hourto 24 hours, preferably 4 hours to 8 hours. The resultant product hasthe formula:

The compound of formula XIX is reacted with the compound of the formula:

xIx

wherein X is halogen, to obtain a compound of the formula:

The hydrogenation may be run in absolute alcohol using a platinum oxidecatalyst.

To obtain compounds of formula I wherein R is and R is lower alkyl, achlorosulfonyl substituted acetanilide of formula XIII is first preparedas described above. The compound of formula XIII is reacted with anamine having the formula:

NH R, XXI

to yield a compound having the formula:

XXII S-R2 HICIICH3 R HN-F O The reaction can be carried out by firstdissolving the compound of formula XIII in an organic solvent, such asbenzene, and then adding the solution to an icecooled aqueous solutionof an amine of formula XXI. After a short period, the reaction mixtureis heated under reflux for a period of about 30 minutes to 12 hours,preferably about 1 to 3 hours.

Following the procedure described above for conversion of thesulfamylacetanilide of formula XIV to a sulfamyl substituted1,2,4-benzothiadiazine of formula I, but substituting the loweralkylsulfamylacetanilide for the sulfamylacetanilide of formula XIV,yields a compound of formula I wherein R is and R; islewer alk l.Fbfihiitlbh f the pharmaceutically acceptable acidaddillbh salts %f thecompounds of formula I may be.

8 cially the hydrochloride and hydrobromide, sulfate, nitrate,phosphate, tartrate, maleate, fumarate, citrate, succinate,methanesulfonate. benzenesulfonate, toluenesulfonate, and the like.

Compounds having the formula:

2 XXIII 4 lower alkyl are specifically contemplated. Examples of thecompounds of formula XXIII are 7-chloro-4-methyll 4-methylpheny)-1,2,4-benzothiadiazin-3(4I-I)-one, l-oxide; 6-chloro-4-ethyl- 1-(4-ethoxyphenyl )-7sulfamyll,2,4-benzothiadiazin-3(4I-I)-one, l-oxide;and 6-trifluoromethyl-4-propyl-l-phenyl-1,2,4-benzothiadiazin-3(4H)-one,l-oxide. Compounds having the formula:

l 4 lower alkyl NH XXIV are specifically contemplated. Examples of thecompounds of formula XXIV are 7-nitro-4-( 3-aminopropyl l -phenyll,2,4-benzothiadiazin-3(4H)-one, l-oxide; 7-methyl-4-( Z-aminoethyl l-phenyl- 1 ,2,4-benzothiadiazin-3(4H)-one, l-oxide; 4-( 3-aminopropyl l-(4-trifluoromethylphenyl l,2,4-benzothiadiazin-3(4H)-one, l-oxide; and6-methoxy-4-( 3-aminopropyl l -phenyl-7-sulfamyll,2,4-benzothiadiazin-3(4H)-one, l-oxide.

Compounds having the formula:

xxv 2 s R C]:

N R \O lower alkyl Nlower alkyl H lower alkyl-N (lower alkyl) arespecifically contemplated. Examples of the compounds of formula XXVI are6-methyl-4-[3(diethylamino )propyl]- l3-nitrophenyl)-1,2,4-benzothiadiazin-3(4H)-one, oxide; Y 7-chloro-4- 2-(dimethylamino )ethyl 1 -phenyll,2,4-benzothiadiazin-3( 4H)-one, l-oxide;4-[2-(diisobutylamino)ethyl]- 1 -phenyl- 1,2,4-benzothiadiazin-3(4H)-one, l-oxide. Compounds having the formula:

XXVII 2 S\\ l R 2 R f a 4 lower alkyl-N Z EXAMPLE 17-Chloro-4-[2-(dimethylamino)ethyl]-1 -phenyll ,2,4- benzothiadiazin-3(4H )-one, l-oxide A. 4-Chloro-2-(phenylthio)benzoyl chloride To astirred suspension of 59.2 g. (0.224 mole) of 4-chloro-2-(acid in 200-(phenylthio)benzoic of benzene is added dropwise 41.6 g. (0.35 mole) ofthionyl chloride during a 1 hour period, and the reaction mix ture isheated under reflux for an additional hour. The reaction mixture is thenconcentrated to dryness under reduced pressure, and the residue isrecrystallized from 300 ml. of boiling hexane to yield 41.9 g. of paleyellow product, melting point 94C-96C. Anal. Calcd for C H Cl OS: C,55.13; H, 2.85; C1,

25.04; Found: C, 55.37; H, 2.73; CI, 24.81.

B, 4-Chloro-2-(phenylthio)acetophenone A stirred mixture of 3.76 g.(0.156 gram-atom) of magnesium tumings, ml. of absolute ethanol, and afew drops of carbon tetrachloride is warmed until the reaction has beeninitiated. A mixture of 25.0 g. (0.155

mole) of diethylmalonate, 9.3 ml. (0.31 mole in toto) of absolutealcohol, and 150 ml. of anhydrous ether is added rapidly. A gummyreaction product separates from solution. This is heated under refluxconditions for 3 hours. A solution of 39.7 g. (0.14 mole) of 4-chloro-2-(phenylthio)benzoyl chloride in 200 ml. of

ether is then run in rapidly from a dropping funnel.

After stirring for an additional 3 hours, the complexed addition productis decomposed with a solution of 25 ml. of concentrated sulfuric acid in200 ml. of water.

The addition product is then extracted into 500 ml. of

chloroform, and the chloroform extract dried and concentrated to give asolid, melting point 106C-108C.

This solid is heated in a mixture of 20 ml. of concentrated sulfuricacid, 50 ml. of water, and 200 ml. of

acetic acid under reflux conditions for 2 hours. The acetic acid is thensubstantially removed by distillation under reduced pressure. Additionof a further m1. portion of water and cooling leads to crystallizationof 35.8 g. of the ketone, melting point 65C66C, after recrystallizationfrom aqueous alcohol.

Anal. Calcd for C H CIOS: C, 63.98; H, 4.22; Cl,

13.40; Found: C, 63.79, H, 4.46; Cl, 13.40.

C. 4-Chloro-2-(phenylsulfinyl)acetophenone To a vigorously stirredsolution of 199 g. (0.75 mole) of 4-chloro-2-(phenylthio)acetophenone in2 liters of 1,2-dimethoxyethane (glyme) is added a solution of 176.5 g.(0.825 mole) of sodium periodate; the mixture is heated at 40C for 7days. The mixture is then filtered from the inorganic materials and theglyme distilled from the filtrate to give a slurry of crystals. Theseare filtered and this mixture of sulfoxide and starting material isseparated from the inorganic contaminants by extraction into abs.ethanol. After filtration and concentration, the residue is dissolved in1.5 liters of boiling hexane to give (after cooling and filtration) 91.8g. of product, melting point 129C-130C.

Anal. Calcd for C H ClO S: C, 60.33; H, 3.97; S,

11.50; Found: C, 60.07; H, 4.18; S, 11.74.

D. 4-Chloro-2-(phenylsulfonimidoyl)acetanilide and7-Chloro-3-methyll-phenyll ,2,4-benzothiadiazinel oxide A stirred,cooled (0C) solution of 7.0 g. (0.025 mole) of4-chloro-2-(phenylsulfinyl)acetophenone in 100 ml. of chloroform iscombined with 14.0 ml. of concentrated sulfuric acid and treateddropwise with 69 ml. (0.075 mole) of a 1.08 N chloroform solution ofhydrazoic acid. After stirring for 1 hour, the ice bath is removed andthe mixture is warmed to 40C; stirring is continued for an additional 30minutes. The reaction mixture is then cooled, added to 100 ml. of icewater, neutralized with solid sodium bicarbonate, the chloroform layerseparated, and, after drying over anhydrous magnesium sulfate,concentrated to dryness. On recrystallization from aqueous alcohol, theresidue gives 3.6 g. of 4-chloro-2-(phenylsulfonimidoyl)acetanilide,melting point 141C142C.

Anal. Calcd for C H CIN O S /2 H O: C, 52.90; H,

4.44; N, 8.82; S, 10.09; Found: C, 53.24; H, 4.18; N, 8.45; S, 10.53.

On standing, the mother liquors from the above recrystallization deposit0.6 g. of 7-chloro-3-methyl-1- phenyl- 1 ,2,4-benzothiadiazinel-oxide,melting point 151C- 152C.

Anal. Calcd for C H ClN OS: C, 57.84; H, 3.81; N,

9.64; Found: C, 57.75; H, 4.07; N, 9.61.

E. 4-Chloro-2-(phenylsulfonimidoyl)aniline hydrochloride Following theprocedure of (D) but using 83.8 g. (0.30 mole) of4-chloro-2-(phenylsulfinyl)acetophenone, 500 ml. of chloroform, 250 ml.of concentrated sulfuric acid, and 472 ml. of a 1.4 N chloroformsolution of hydrazoic acid, 79.7 g. of a mixture of '4-'chloro-2-(phenylsulfonimidoyl)acetonilide and 7-chloro-3- methyll-phenyl- 1,2,4-benzothiadiazinel-oxide is obtained. This mixture is stirred andheated under reflux conditions in 450 ml. of sodium hydroxide solutionfor 3.5 hours. After the mixture is cooled, it is extracted with 500 ml.of chloroform, and the extract is dried and concentrated to give 68.7 g.of a viscous oil. This is extracted with 500 ml. of anhydrous ether. Theextract is filtered and cooled in ice. While the extract is cooling inice, it is treated in a dropwise manner with a slight excess (to pH 4.0)of ethereal hydrogen chloride to give 55.2 g. of product, melting point217C-2 19 C after filtration and drying.

F. 7-Chlorol-phenyl-1,2,4-benzothiadiazin- 3(4H)-one, l-oxide A stirredmixture of 18.80 g. (0.062 mole) of 4-chloro-2-(phenylsulfonimidoyl)aniline hydrochloride and 10.6 g. (0.065mole) of l,l-carbonyldiimidazole in 500 ml. of o-dichlorobenzene isheated under reflux conditions for 2 hours, filtered, and cooled. Theglistening plates which form are filtered, washed with water, and driedto yield 11.28 g. of product, melting point 261C262C.

A sample for analysis is recrystallized from alcohol and the meltingpoint is unchanged.

Anal. Calcd for C H ClN O S: C, 53.33; H, 3.10; N,

9.57; Found: C, 53.43; H, 3.22; N, 9.74.

G. 7-Chloro-4-[2-( dimethylamino)ethyl]- l-phenyl-1,2,4-benzothiadiazin-3(4H )-one, l-oxide To a stirred suspension of 6.6g. (0.0225 mole) of 7-chloro-l-phenyl-1,2,4-benzothiadiazin-3(4H)-one,l-oxide in 200 ml. of dried and distilled glyme is added (at 0C) 1.2 g.(0.025 mole) of 50% dispersion of sodium hydride in mineral oil in smallportions. After 0.5 hours, 30 ml. of a 1.04 N solution of2-dimethylaminoethyl chloride (0.031 mole) is added dropwise during a 15minute period and the mixture is heated under reflux conditions for 6hours. The reaction mixture is then filtered, and concentrated todryness to yield 7- chloro-4-[2-(dimethylamino)ethyl]-l-phenyl-1,2,4-benzothiadiazin-3(4H)-one, l-oxide.

EXAMPLE 2 7-C1iloro-4-[2-(dimethylamino)ethyl]-l-phenyl-1,2,4-benzothiadiazin-3(4H)-one, l-oxide, hydrochloride l :1

7-Chloro-4-[2-( dimethylamino )ethyl]- l-phenyl-1,2,4-benzothiadiazin-3(4H)-one, l-oxide (8.2 grams) is dissolved in 100ml. of acetonitrile, and treated with 7.5 ml. (0.03 mole) of 4 Nethereal hydrogen chloride. The title compound which is, separated isrecrystallized two times from abs. ethanol and dried at 100C in vacuo togive 3.0 g. of a colorless product, melting point 261C-262C. dec. Anal.Calcd for C H CIN O S HCl: C1, 17.72; S,

8.01; Found: Cl, 17.92; S, 7.88.

EXAMPLE 3 7-Chloro-4-[ 3-( dimethylamino )propyl]- l-phenyl-1.2.4benzothiadiazin-3(4H)-one, l-oxide. hydrochloride To an ice-cooled,stirred suspension of 11.23 g (0.038 mole) of7-chloro-l-phenyl-1.2,4-benzothiadiazin-3(4H)-one, l-oxide (prepared asdescribed in Example 1. parts A-F) in 250 ml of dried and distilledglyme. 2.22 g (0.046 mole) of a 50% dispersion of sodium hydride inmineral oil is gradually added. The

mixture is stirred for 30 minutes and then 45.5 ml (0.05

mole of a 1.1 N solution of 3-dimethylaminopropyl chloride is addeddropwise over a 15 minute period,

followed by heating under reflux conditions for 3 hours. The mixture isfiltered, concentrated to dryness,

and the residue partitioned between m1 of N hydrochloric acid and 100 mlof chloroform. The aqueous phase is separated, made alkaline with sodiumbicarbonate, and the product extracted into 250 ml of chloroform. Theextract is dried and concentrated to give 1 1.5 g of the free base ofthe product in the form of a viscous gum.

Anal. Calcd for C H ClN O S 2 H O: C, 52.22; H,

5.84; N, 10.15; Found: C, 51.61; H, 5.35; N, 10.49. The crude base isdissolved in 50 ml of acetonitrile and cooled in an ice bath. 10 ml of4N ethereal hydrogen chloride is added dropwise. The solution isconcentrated to one-half volume and cooled. The tan colored solid (9.15g, melting point 227C- 229C, dec.) is filtered and recrystallized fromabs. ethanol to give 5.56 g of colorless product, melting point248C-249C, dec., after drying at 100C for 4 hours.

Anal. Calcd for C H ClN O S HCl: C, 52.17; H,

5.11; N, 10.14; Found: C, 51.91; H, 5.20; N, 10.04.

EXAMPLE 4 6-Ch1oro-4-(dimethylamino)propylJ-1-phenyl-7-sulfamyl- 1 .2,4-benzothiadiazin-3(4H )-one, l-oxide hydrochloride A.5-Chloro-2-(phenylthio)acetanilide To a stirred solution of 235.7 g. 1mole) of 4-chloro- 2-(phenylthio)aniline, (prepared by the proceduredescribed in US. Pat. No. 3,188,320), in 1 liter of chloroformcontaining 87.0 g. 1.1 mole) of pyridine, 1 12.3 g. 1.1 mole) of aceticanhydride is added over a 1 hour period. The mixture is heated underreflux for 1 hour. The cooled reaction mixture is then extractedsuccessively with 1 liter portions of N-hydrochloric acid and N sodiumcarbonate, dried (anhydrous magnesium sulfate), and concentrated todryness to give the above product.

B. 5-Chloro-4-chlorosulfonyl-2-( phenylthio )acetanilide A mixture of250 g. (0.9 mole) of 5-chloro-2- (phenylthio)acetanilide and l 16.52 g.1.0 mole) of chlorosulfonic acid in 2.5 liters of o-dichlorobenzene isheated at C- C for 2 hours in an oil bath. The reaction mixture iscooled, washed with 1 liter of cold sodium carbonate solution, washedwith water and then dried using magnesium sulfate. Removal of thesolvent by distillation under vacuum yields the product.

C. 5-Chloro-2-(phenylthio)-4-sulfamylacetani1ide A solution of 276.0 g.(0.75 mole) of 5-chloro-4- chlorosulfonyl-2-(phenylthio)acetanilide in 2liters of benzene is added dropwise to 1 liter of concentrated aqueousammonia, with cooling in an ice bath, over a period of 1 hour. After theaddition is complete, the ice bath is removed and the mixture is heatedto reflux and stirred vigorously for an additional 2 hours. The benzeneis removed by steam distillation, the residual material is cooled, thepH is adjusted to 6.5, and the product is filtered and dried.

D. 5Chloro-2-( phenylsulfinyl )-4-sulfamylacetanilide 231 g. (0.65 mole)of 5-chloro-2-(phenylthio)-4-sulfamylacetanilide is stirred in 3.5liters of glyme. A solution of 154 g. (0.72 mole) of sodium periodate in1500 ml. of water is added to the mixture dropwise over a 2 hour period.The mixture is then stirred vigorously for 24 hours while heating underreflux conditions. The reaction mixture is filtered from the inorganicmaterials, and concentrated under reduced pressure to remove the glyme.The slurry of crystalline material remaining is cooled, filtered, andthe solid material extracted with absolute alcohol, filtered to removeinsoluble inorganic contaminants, and the extract partiallyconcentrated, cooled, and filtered to yield the product.

E. -Chloro-2-(phenylthiosulfinyl)-4-sulfamylaniline A solution of 186.8g. (0.5 mole) of 5-chloro-2- (phenylsulfinyl)-4-sulfamylacetanilide in1.5 liters of aqueous sodium hydroxide is heated under reflux conditionsfor 3 hours, cooled, the pH adjusted to 6.5-7 with N hydrochloric acid,and the separated product filtered, dried, and recrystallized fromethanol.

F. 5-Chloro'-2-(phenylsulfonimidoyl)-4-sulfamylaniline A stirred, cooled(0C) solution of 149.0 g 0.45

mole) of 5-chloro- 2-( phenylthiosulfinyl )-4-sulfamylaniline in 1.5liters of chloroform is combined with 300 ml. of concentrated sulfuricacid and treated dropwise with 450 ml. of a l N chloroform solution ofhydrazoic acid. After stirring for 1 hour, the ice bath is removed andthe mixture is warmed to 40C; stirring is continued for an additional 30minutes. The reaction mixture is then cooled, added to 100ml. of icewater, neutralized with solid sodium bicarbonate, the chloroform layerseparated, and, after drying over anhydrous magnesium sulfate,concentrated to dryness. Recrystal lization from aqueous alcohol yieldsthe product.

G. 6-Chlorol-phenyl-7-sulfamyll ,2,4-benzothiadiazine-3(4H )-onel-oxideA stirred mixture of 34.5 g. (0.1 mole) of 5-chloro-2-(phenylsulfonimidoyl)-4-sulfamylaniline and 16.2 g. (0.1 mole) ofl,l'-carbonyldiimidazole in 500 ml. of o-dichlorobenzene is heated underreflux conditions for 2 hours, filtered, and cooled, yielding theproduct.

H. 6-Chloro-7-( N ,N-dibenzyloxycarbonylsulfamyl l-phenyl-1,2,4-benzothiadiazine-3 4H )-one- 1 -oxide A stirred mixture of 37.2 g.0.1 mole) of 6-chlorolphenyl-7-sulfamyll ,2,4-be nzothiadiazine-3 4H)-onel-oxide, 34.0 g. (0.2 mole) of benzyl chloroformate, 13.8 g. (0.1mole) of potassium carbonate, and 500 ml. of acetone of heated underreflux conditions for hours, filtered, and concentrated to dryness. Theresidual material is taken up into 500 ml. of dichloromethane, extractedwith 100 ml. of N aqueous sodium hydroxide, washed with water, dried,and concentrated under pressure.

I. 6-Chloro-7-( N,N-dibe nzyloxycarbonylsulfamyl )-4- [3-( dimethylamino)propyl l-phenyll ,2,4-benzothiadiazin-3( 4H)-onel -oxide To an icecooled stirred suspension of 50.6 g. (0.08 mole) of6-chloro-7-(N,N-dibenzyloxycarbonylsulfamyl l-phenyll.2,4-benzothiadiazine-3(4H )-one 1 oxide in 1 liter of dried anddistilled glyme is gradually added 3.7 g. (0.88 mole) of a 57%dispersion of sodium hydride in mineral oil..After stirring for minutes,140 ml. (0.1 mole) of a 1.4 N solution of dimethylaminopropyl chloridein benzene is added dropwise over a 1 hour period, and the mixture isheated under reflux conditions for 5 hours. It is then filtered,concentrated, and the residue partitioned between 250 ml. of cold Nhydrochloric acid and an equal volume of ether. The acid phase is madealkaline with a slight excess of concentrated aqueous ammonia and theproduct is extracted with two 250 ml. portions of chloroform, the

14 combined extracts dried and concentrated to dryness to yield theproduct. I

J. 6-Chloro-4-[3-(dimethylamino)propyl]-l-phenyl- 7-sulfamyl-1,2,4-benzothiadiazin-3( 4H )-onel-oxide A solution of 50.3 g. (0.07mole) of 6-chloro-7- (dibenzyloxycarbonylsulfamyl )-4-[ 3-(dimethylamino pr0pyl]-l-phenyl-1,2,4-benzothiadiazin-3(4H)-one-loxide in1 liter of abs. ethanol is hydrogenated at an initial pressure of 50p.s.i. in the presence of 1.0 g. platinum oxide for 24 hours. Thereaction mixture is then filtered, concentrated to dryness under an oilpump vacuum, the residue reprecipitated from dilute aqueous sodiumhydroxide solution, filtered, and dried to yield the product.

K. 6-Chloro-4-[3-(dimethylamino)propyl]-l-phenyl- 7-sulfamyll,2,4-benzothiadiazin-3( 4H )-onel-oxide hydrochloride A solution of 22.8g. (0.05 mole) 6-chloro-4-[3-(dimethylamino)propyl]-l-phenyl-7-sulfamyl-1,2,4-benzothiadiazin-3(4H)-one-l-oxide in ml. of acetonitrile is treated with100 ml. of 2.5 N ethereal hydrogen chloride while stirring and coolingin an ice bath. The solid is filtered and dried to yield the product.

EXAMPLE 5 6-Chloro-7-methylsulfamyll -phenyll ,2,4-benzothiadiazin-3(4H)-one, l-oxide A. 5-Chloro-4-rnethylsulfamyl-2-( phenylthio)acetanilidei A solution. of 188 g (0.5 mole) of 5-chloro-4- chlorosulfamyl-2-(phenylthio )acetanilide (prepared as described in Example 4, parts A andB) in 1 liter of benzene is added dropwise to 1 liter of ice-cooled,vigorously stirred 40% aqueous methylamine solution over a period of 1hour. The ice bath is then removed and the reaction mixture is heatedunder reflux for 2 hours, concentrated under reduced pressure to removethe benzene and excess methylamine, and the pH is adjusted to between 6and 7 to yield the title compound.

B. 5-Chloro-4-methylsulfamyl-2-(phenylsulfinyl) acetanilide To asolution of 148 g. (0.4 mole) of 5-chloro-4-methylsulfamyl-2-(phenylthio)acetanilide in 1 liter of acetic acid isadded 37.5 ml. (0.44 mole) of a 40% solution of hydrogen peroxide over a1 hour period while stirring vigorously. The mixture is allowed to standfor 24 hours, and then poured into 5 liters of ice water to yield thetitle compound.

C. 5-Chloro-4-methylsulfamyl-2-(phenylsulfinyl) aniline A solution of 116 g. (0.3 mole) of5-chloro-4-methylsulfamyl-2-(phenylsulfinyl)acetanilide in 1 liter of10% sodium hydroxide solution is heated under reflux conditions for 3hours, cooled, and the pH adjusted to 6.5 with 20% hydrochloric acid toyield the title compound.

D. 5-Chloro-4-methylsulfamyl-2-(phenylsulfonimidoyl) aniline To astirred, cooled (0C) mixture of 69.0 g. (0.25 mole) of5-chloro4-methylsulfamyl-2-( phenylsulfinyl) aniline, l'liter ofchloroform and 200 ml. of concentrated sulfuric acid is added 250 ml. ofa N solution of hydrazoic acid in chloroform over a 2 hour period. Afterstirring for 3 hours, 500 g. of crushed ice is added, the reactionmixture is neutralized with sodium bicarbonate, the chloroform layer isseparated, and the -cont1nued Example Column l Column ll Column lllthiadiazin-3( 4H )-one. l-oxide 27 4-chloro-Z-[3-methylmethylaminopropyl 7-chloro-4-l 3 methylamino )propyllphenyllthiolbenzoic acid chloride -l-(3-methylphenyl)-l .24-henzothiadiazin-3(4H)-one. l-oxide 28 4-chloro-2-[Z-chlorolmorpholinoethyl 7-chloro-4-[2 morpholino )ethyl]phenylnhiolbenzoic acid chloride-I-(2-chlorophenyl)-l.2,4-benzothiadiazin-3( 4H l-one. l-oxide 294-chlor0-[ Z-fluoro 2-pyrrolidinoethyl 7-chloro-4-[2-(pyrrolidino)ethyl] phenyl )thio1benzoic chloride 1 2fluorophenyl I 2.4-benzoacidthiadiazin-3(4H)-one. l-oxide 30 4-(trifluoromethyl)- methyl iodide7-(trifluoromethyl)4methyl-l- 2-( phenylthio )benzoic phenyl-l.2.4-benzothiadiazin-3(4H acid one, l-oxide 31 4-nitro-2-(phenylthi0)ethyl iodide 7-nitro-4-ethy|-l-phenyl-1,2,4-

benzoic acid benzothiadiazin-3(4H)-one. l-oxide 32S-chloro-Z-(phenylthio) methyl iodide 6-chloro-4-methyll-phenyl-l .2.4-

benzoic acid benzothiudiazin-3(4H) one. l-oxide 334-chloro-2-[(2-chloromethyl iodide 7-chloro-4methyll-(2-chlorophenyl)thiolbenzoic acid phenyl )-l .2.4-benzothiadiazin- 3(4H)one, l-oxideWhat is claimed is: l. A compound having the structure:

wherein R is lower alkyl, amino-lower alkyl, monoor dilower alkylamino-lower alkyl, or imino-lower alkyl wherein the imino group has theformula:

(C N/ 2 AZ (CH l wherein Z is oxygen, CI-l-R or N-R n is 2 or 3, m is 2or 3, R is hydrogen. phenyl, or benzyl and R is hydrogen, lower alkyl,phenyl, or phenyl substituted with halogen, lower alkyl, lower alkoxy,or trifluoromethyl;

R is phenyl or phenyl substituted with halogen, nitro,

trifluoromethyl, lower alkyl or lower alkoxy; R is hydrogen, halogen,nitro, cyano, trifluoromethyl, lower alkyl or lower alkoxy; and R ishydrogen, or 8n where R is hydrogen or lower alkyl; and pharmaceuticallyacceptable acid-addition salts thereof.

2. A compound in accordance with claim 1 having the formula:

4. A compound in accordance with claim 1 having the formula:

lower alkyl-Ig-lower alkyl 5. A compound in accordance with claim 1having the formula:

4 lower alkyl-N(lower alkyl) 65 6. A compound in accordance with claim 1having the formu la:

lower alkyl N Z 7. A compound in accordance with claim 1 wherein R ishydrogen.

8. A compound in accordance with claim 1 wherein 'UINFEED STATES PATENTAND TRADEMARK OFFICE (IERTEHQATE 0F (IORRECTION PATENT NO. 1 3 92 {)ATEDDecember 16, 1975 |NVENTOR(S) Francis Alexander Sowinski, B. RichardVogt b it is certified that 8;){2-385'5 in he abc-veiden.fified patentand that said Letters Patent are Hereby ccrrecied as shown below:

Column 2, line 4, delete "hydrogen and".

Columnl2, line 27, "6-Chloro-4- (dimethylamino) shou b" read -6Chloro4[3- (dimethylamino).

Column 17, line 46, "n is 2 or 3," should read n is l, 2 or 3,

Column 17, line 55, please omit"8n! at the end of the line.

Column 20, in the structure, please omit "is" before it Signed andScaled this thirtieth D3 y of March I 976 [SEAL] Arrest.-

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner uj'larentxand Trademarks UNII'ED SIATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORECTION PATENT NO. I 3 92 977 AT December 16, 1975 INVENTOR S FrancisAlexander Sowinski, B. Richard Vogt It is cerizfied thai sear apeeaz'sin he ahoveidentfied patent and that said Letters Patent are herebycorrected as shown below:

Column 2, line 4, delete "hydrogen and".

Columnl2, line 27, "6-Chloro-4-(dimethylamino)" shou read --6-Chloro4[3(dimethylamino)-.

Column 17, line 46, "n is 2 or 3," should read n is l, 2 or 3,

Column 17, line 55, please omit"8n'.' at the end of the line.

Column 20, in the structure, please omit "is" before it.

Signed and Sealed this thirtieth Day of March 1976 [SEAL] A ttest.

RUTH C. MASON C. MARSHALL DANN Atlesll'ng Officer (ummissimu'rofPare'nts and Trademarks

1. A COMPOUND HAVING THE STRUCTURE:
 2. A compound in accordance withclaim 1 having the formula:
 3. A compound in accordance with claim 1having the formula:
 4. A compound in accordance with claim 1 having theformula:
 5. A compound in accordance with claim 1 having the formula: 6.A compound in accordance with claim 1 having the formula:
 7. A compoundin accordance with claim 1 wherein R4 is hydrogen.
 8. A compound inaccordance with claim 1 wherein R4 is
 9. The compound in accordance withclaim 1 having the name7-chloro-4-(2-(dimethylamino)ethyl)-1-phenyl-1,2,4-benzothiadiazin-3(4H)-one, 1-oxide, hydrochloride.
 10. The compound in accordance with claim1 having the name7-chloro-4-(3-(dimethylamino)propyl)-1-phenyl-1,2,4-benzothiadiazin-3(4H)-one, 1-oxide, hydrochloride.
 11. The compound in accordance with claim1 having the name6-chloro-4-(3-(dimethylamino)propyl)-1-phenyl-7-sulfamyl-1,2,4-benzothiadiazin-3(4H)-one-1-oxide, hydrochloride.